The histamine H3 receptor is located as a presynaptic autoreceptor in the central nervous system and as a presynaptic heteroreceptor on serotonergic, noradrenergic, dopaminergic, and cholinergic neurons. The histamine H3 receptor is also located peripherally in tissues such as vascular smooth muscle cells.
Proposed uses of histamine H3 antagonists include the treatment or prevention of dementia, Alzheimer's disease (Panula et al. Abstr. Society Neuroscience, 1995, 21:1977), epilepsy (Yokoyama et al. Eur. J. Pharmacol., 1993, 234:129), sleep/wake disorders (Lin et al., Br. Res., 1990, 523, 325; Monti et al., Eur. J. Pharmacol., 1991, 205, 283) including narcolepsy, insomnia, and jet lag, eating disorders (Machidori et al. Brain Research, 1992, 590:180), motion sickness, vertigo, attention deficit hyperactivity disorder, learning and memory disorders (Barnes et al. Abstr. Society Neuroscience, 1993, 19:1813), schizophrenia (Schlicker et al. Naunyn Schmiedeberg's Arch. Pharmacol., 1996, 353:325), and sequelae associated with post-ischemic reperfusion and hypertension (Imamura et al., J. Pharmacol. Expt. Ther., 1994, 271, 1259). H3 antagonists are also useful to treat or prevent neurogenic inflammation such as migraine (McLeod et al., Abstr. Society Neuroscience, 1996, 22, 2010), asthma (Ichinose et al., Eur. J. Pharmacol., 989, 174, 49), obesity, allergic rhinitis, substance abuse, bipolar disorders, manic disorders, and depression. Histamine H3 antagonists alone or in combination with a histamine H1 antagonist are believed to be useful in the treatment of upper airway allergic response or allergic rhinitis (see, e.g., U.S. Pat. Nos. 5,217,986, 5,352,707, and 5,869,479).
As noted, the prior art related to histamine H3 ligands was comprehensively reviewed recently (“The Histamine H3 Receptor-A Target for New Drug”, Leurs, R., and Timmerman, H., (Editors), Elsevier, 1998). Within this reference the medicinal chemistry of histamine H3 agonists and antagonists was reviewed (see Krause et al. and Phillips et al., respectively). Thus the importance of an imidazole moiety containing only a single substitution in the 4 position was noted together with the deleterious effects of additional substitution on activity. Particularly methylation of the imidazole ring at any of the remaining unsubstituted positions was reported to strongly decrease activity.
More recently several publications have described histamine H3 ligands that do not contain an imidazole moiety. Examples include Ganellin et al Arch. Pharm. (Weinheim, Ger.) 1998, 331, 395; Walczynski et al Arch. Pharm. (Weinheim, Ger.) 1999, 332, 389; Walczynski et al Farmaco 1999, 684; Linney et al J. Med. Chem. 2000, 2362; U.S. Pat. No. 5,352,707; PCT Application WO99/42458, published Aug. 26, 1999; and European Patent Application 0978512, published on Feb. 9, 2000.